JP7444901B2 - 4-[5-[(RAC)-1-[5-(3-chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1 for use in the prevention and/or treatment of pain in animals, 2,4-triazol-3-yl]pyridine - Google Patents

Description

The present invention is for use in the prevention and/or treatment of chronic and/or peripheral pain and/or pain associated with arthritis, such as osteoarthritis, in animals such as dogs, cats or horses, or b) GERD. or c) 4-[5-[(rac)-1-[5-(3-chlorophenyl)-3-isoxazolyl]ethoxy]- for use in the prevention and/or treatment of such pain in combination with anxiety. 4-Methyl-4H-1,2,4-triazol-3-yl]pyridine (TT00) or its pharmaceutically acceptable salts, diastereomers, enantiomers, isotopes, prodrugs or metabolites, or their The present invention relates to a mixture or a pharmaceutical composition containing the TT00.

Pain is an area of primary interest in veterinary medicine. The most commonly used pain relief in dogs is the use of non-steroidal anti-inflammatory drugs (NSAIDs). However, long-term treatment with NSAIDs in case of osteoarthritis causes major side effects. Currently, NSAIDs are used in 75% of animals suffering from osteoarthritis in the EU.

Typical side effects of NSAIDs in dogs are vomiting, anorexia, depression and diarrhea. Serious side effects have also been reported, such as gastrointestinal ulcers, liver/kidney failure, and even death.

TT00, or 4-[5-[(rac)-1-[5-(3-chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine

, and TT002, or 4-[5-[(1S)-1-[5-(3-chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl ]Pyridine

, and TT001, or 4-[5-[(1R)-1-[5-(3-chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl ]Pyridine, CAS number 934282-55-0,

has the molecular formula C ₁₉ H ₁₆ ClN ₅ O ₂ and a relative molecular weight of 381.8 (base).

These compounds are selective non-competitive antagonists at the metabotropic glutamate receptor subtype 5 (mGluR5) and have been shown to be useful in the oral treatment of chronic pain syndromes of neuropathic origin, anxiety and gastroesophageal reflux disease (GERD) in humans. was developed for. Development for all indications was discontinued after clinical trials.

TT00 affects mGluR5 receptors in the central nervous system, resulting in central pain relief. Arthritis, such as osteoarthritis, causes pain in the peripheral nervous system.

In clinical development, dogs have been used for toxicity studies, but efficacy studies for pain indications have not been conducted. A bibliographic search found no disclosures of the treatment of pain in dogs, cats or horses or the combination of pain and anxiety or pain and GERD for this molecule.

Although rodent animal models can predict efficacy in humans, no studies have been presented in which rodent models predict outcome in dogs. There are few larger animal pain models.

Comparison of species metabolites Many things must be cleared up before a molecule becomes a drug candidate. Two important steps that a molecule must go through are species compatibility through metabolite profile evaluation.

In the non-clinical portion of drug development, studies are designed to determine metabolite profiles and characterize selected metabolites produced after incubation of the molecule in rat and human hepatocytes. The results obtained will be used to compare human liver metabolism with the rodent model used in safety studies.

One method used is to harvest rat and human hepatocytes and incubate them with the molecules. The metabolite profile in the supernatant is recorded by liquid chromatography. Selected metabolites are characterized by accurate mass spectrometry. There may be more than ten different metabolites derived from hepatic metabolism.

Metabolite profiles should be similar between the two species. If this is not the case, the predictability of the rodent model for humans is not obvious and the molecule likely will not be further developed.

It is also well known that for certain indications, such as inflammatory diseases, the predictability of rodent models relative to humans is very low. (PNAS | February 26, 2013 | vol. 110 | no. 9 | 3507-3512, Genomic responses in mouse models poorly mimic human infrastructure diseases)

This also applies to clinical pain. Unfortunately, rodent biology often cannot accurately predict the biology and pharmacology of clinical pain conditions in humans. (Blackburn-Munro 2004; Le Bars et al. 2001, Translational Pain Research: From Mouse to Man. Kruger L, Light AR, editors. Boca Raton, FL: CRC Press/Taylor &Francis; 2010.Chapter 17 Large Animal Models for Pain Therapeutic Development , Darrell A. Henze and Mark O. Urban).

Based on rodent models, both drug metabolism and cross-species metabolite profiles, and the difficulty of predicting response in humans, one skilled in the art will be able to predict the activity of a compound in relevant species. The efficacy and toxicity of a drug in one species cannot be predicted based on data from another species unless specific studies are conducted to verify.

Furthermore, there are no published data on TT001 and liver metabolism and metabolite profiles in rats and dogs, and certainly not for rats compared to cats and horses.

There are many examples of drugs that have different effects in different species.

Tramadol is widely used as an analgesic with good efficacy in humans, but no effects occur in dogs. (J Am Vet Med Assoc. 2018 Feb 15; 252(4): 427-432.doi:10.2460/javma.252.4.427., Lack of effectiveness of tramadol hydrochloride e for the treatment of pain and joint dysfunction in dogs with chronic osteoarthritis., Budsberg SC, Torres BT, Kleine SA, Sandberg GS, Berjeski AK.)

Tramadol is also known to have adverse effects in dogs, causing them to lose concept and balance and appear as if they are "high." There are also drugs used in humans that are toxic to animals. Examples of this are phenolic drugs, including acetaminophen and aspirin, which should not be given to cats. (Shrestha B, et al., Evolution of a major drug metabolizing enzyme defect in the domestic cat and other felidae: phylogen etic timing and the role of hypercarnivory, Life Sci.2006 Nov 25;79(26):2463-73.Epub 2006 Oct 5).

Court MH, Feline drug metabolism and disposition: pharmacokinetic evidence for species differences and molecular mechanisms, V et Clin North Am Small Anim Pract. 2013 Sep;43(5):1039-54. doi:10.1016/j. cvsm. 2013.05.002 shows pharmacokinetic evidence of differences in drug excretion rates between cats, dogs, and humans in Figure 1. Cats for typical drugs that are primarily excreted by conjugation (glucuronidation, sulfation and glycation), oxidation (CYP enzymes), or are excreted primarily unchanged in the urine and/or bile; A comparison of published elimination half-life values in dogs and humans is shown. All values are expressed as a ratio of human values. Complete pharmacokinetic data and literature references for acetylsalicylic acid, propofol, acetaminophen, carprofen and piroxicam are shown in Table 1.

Particularly in the case of NSAIDs, some are more or less deadly, while others work well. One difficulty with NSAIDs is that both deadly and good NSAIDs can come from the same chemical group/class. A good example of this is ibuprofen, which is toxic to dogs and cats. Ibuprofen is a propionic acid derivative and belongs to the same chemical group as ketoprofen, bedaprofen and carprofen, which are administered to all animals.

Further examples are listed below.

Dog NSAIDs (e.g. Advil, Aleve and Motrin)
Although these medications are safe for humans, even one or two pills can cause serious harm to pets. Dogs, cats, birds and other small mammals (ferrets, gerbils and hamsters) can develop severe gastric and intestinal ulcers and renal failure.

Acetaminophen (e.g., tylenol)
When it comes to analgesics, acetaminophen (eg, tylenol) is certainly common. This drug is very safe, even for children, but this is not the case for pets, especially cats. One regular strength tablet of acetaminophen can cause damage to a cat's red blood cells, limiting their ability to carry oxygen. In dogs, acetaminophen causes liver failure and, at high doses, red blood cell damage.

Antidepressants (e.g., Effexor, Cymbalta, Prozac, Lexapro)
These antidepressants are sometimes used in pets, but overdosing can result in serious neurological problems such as sedation, loss of coordination, tremors and seizures. Some antidepressants also have stimulant effects, resulting in dangerously high heart rate, blood pressure, and body temperature. Pets, especially cats, seem to enjoy the taste of Effexor and often eat the entire pill. Unfortunately, just one pill can cause serious addiction.

ADD/ADHD drugs (e.g., Concerta, Adderall, Ritalin)
Medications used to treat attention deficit disorder/attention deficit hyperactivity disorder include powerful stimulants such as amphetamines and methylphenidate. Even minimal ingestion of these medications by pets can cause life-threatening tremors, seizures, increased body temperature and heart problems.

Benzodiazepines and sleep aids (e.g., Xanax, Klonopin, Ambien, Lunesta)
These medications are designed to reduce anxiety and help people sleep better. However, in pets it may have the opposite effect. Approximately half of dogs that take sleep aids become agitated rather than sedated. Additionally, these drugs can cause severe lethargy, loss of coordination (including "drunken" gait), and slowed breathing in pets. In cats, some forms of benzodiazepines can cause liver failure.

Beta-blockers (e.g., Tenormin, Toprol, Coreg)
Beta-blockers are used to treat high blood pressure, but ingesting small amounts of these drugs can cause severe toxicity in pets. Overdosage can cause a life-threatening drop in blood pressure and very slow heart rate.

Cats Drugs that are toxic to cats include acetaminophen (Tylenol), aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve, Anaprox), antidepressants, ADD/ADHD medications, sleep aids (benzodiazepines, Xanax, Ambien), beta-blockers, thyroid hormones, and cholesterol drugs (Lipitor).

There is an unmet need for the treatment of pain in animals such as dogs, cats and horses, especially peripheral pain, especially pain associated with arthritis such as osteoarthritis. There is a need for treatments with reduced side effects such as gastrointestinal toxicity and nephrotoxicity.

WO 2007/040982 discloses the use of TT00, TT001 and/or TT002 in humans for the treatment of neurological, psychiatric or pain disorders. IC50 binding data at mGluR receptors as well as studies on the effects of TT00, TT001 or TT002 on TLESR in healthy dogs in relation to food intake are presented. The results of this study have not been disclosed. There are no clinical data, particularly relating to pain treatment following administration of TT00, TT001 and/or TT002.

Rohof, et al. , Aliment. Pharmacol. Ther. 2012, vol 35, pp 1231-1242 discloses a clinical trial using TT001 to determine its effect on TLESR in healthy volunteers in relation to food intake. The results in Figures 2 and 4 show that only the high dose of 13 mg (approximately 0.19 mg/kg) has some effect 2-3 hours after food intake, but also before food intake. It shows that even after 2 hours there was no significant effect on reflux. Some serious side effects associated with the high dose of 13 mg have been mentioned. No clinical data have been disclosed in relation to pain treatment following administration of TT00, TT001 and/or TT002.

Combination drug therapy (CDT)
There are several studies examining CDT for pain management.

Mao et al. J. Pain, 2011, vol 12, pp 157-166 discloses various combination drug therapies for the treatment of pain. Most treatments use opiates in combination with another painkiller. mGluR5 is not mentioned at all for use in combination therapy such as pain treatment, or in the treatment of pain associated with arthritis such as osteoarthritis.

Mao J. In the review by et al., data are available for CDT in humans, but there is no information regarding treatment in animals. Table 1 lists different combinations and evaluates them with respect to positive or negative results. For osteoarthritis, the oral combination of tramadol and NSAIDs had positive and better pain relief with add-on drugs in humans, but in dogs there was no additive clinical effect of this combination. It should be pointed out that there are studies using the same CDT that have not been reported.

Table 1 of Mao et al also mentions that the oral combination of tramadol and acetaminophen showed positive and better pain relief than the add-on drug in humans. If this CDT is given to a cat, its toxicity can lead to death of the cat.

Meunier N, et al. , Randomized trial of perioperative tramadol for canine sterilization pain management, Vet Rec. 2019 Oct 5;185(13):406. doi:10.1136/vr. 105009. Epub 2019 Jul 18, and Tanaka N, et al. , cDNA cloning and characterization of feline CYP1A1 and CYP1A2, Life Sci. 2006 Nov 25;79(26):2463-73. See also Epub 2006 Oct 5.

There may be a common misconception that combining different drugs alone has an additive effect. In Table 1 of Mao et al, one out of four combinations does not give a positive result. There are even situations where the combination reduces the overall efficacy of pain treatment.

It is clear to those skilled in the art that clinical results in different species do not automatically translate to other species. Therefore, those skilled in the art should and will suggest independent evaluation of efficacy and toxicity for each species. This is clearly also the position of the Medical Products Agency in most countries.

There is an unmet need to treat pain using safe, efficient, and effective drug combinations.

The present invention provides compounds TT00, TT001 and/or TT002, or pharmaceutically acceptable salts, diastereomers, enantiomers, isotopes thereof, for use in the prevention and/or treatment of pain in dogs, cats or horses. , prodrugs or metabolites, or mixtures thereof. In one aspect, the compound is TT001, or its hydrochloride or sulfate salt. In another embodiment, the compound is the hydrochloride salt of TT001. In a further embodiment, the compound is a sulfate salt of TT001. In one embodiment, the animal is a dog.

The characteristics and central mechanism of action of compounds TT00, TT001 and/or TT002 make them candidates for analgesic agents that are quite different from the currently predominantly used NSAIDs.

Compounds TT00, TT001 and/or TT002 exhibit few side effects at the intended doses in dogs, cats and horses. They do not lose efficacy over longer periods of administration. Compounds TT00, TT001 and/or TT002 are known to affect the central nervous system, but show positive effects in the treatment of peripheral pain, such as pain associated with arthritis such as osteoarthritis. Such pain may be chronic. TT00, TT001 and/or TT002 are believed to be effective without serious side effects when used for longer periods of time, such as months or years. TT00, TT001 and/or TT002 are believed to have a reduced potential for side effects, especially when treated over longer periods of time, compared to conventional analgesics currently used in animals, such as NSAIDs. The compounds of the invention are believed to have reduced gastrointestinal and renal toxicity in dogs, cats, and horses, particularly when compared to NSAIDs.

In one aspect, the pain is chronic pain. In another embodiment, the pain is peripheral pain. In further embodiments, the pain is chronic and peripheral pain. In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In another aspect, the pain is chronic and peripheral pain associated with osteoarthritis.

The present invention also provides treatment for both a) pain, such as chronic and/or peripheral pain, and/or pain associated with arthritis, such as osteoarthritis, and b) gastroesophageal reflux disease (GERD) in dogs, cats, or horses. Concerning the compounds TT00, TT001 and/or TT002, or their pharmaceutically acceptable salts, diastereomers, enantiomers, isotopes, prodrugs or metabolites, or mixtures thereof, for use in prophylaxis and/or therapy. .

In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In one aspect, the compound is TT001, or its hydrochloride or sulfate salt. In one embodiment, the animal is a dog. In another embodiment, the animal is a cat or a horse. Because the compounds act on the central nervous system, they can be used to treat and/or prevent pain and GERD simultaneously.

The present invention is also useful for the prevention and/or treatment of both a) pain, such as chronic and/or peripheral pain, and/or pain associated with arthritis, such as osteoarthritis, and c) anxiety in dogs, cats, or horses. Compounds TT00, TT001 and/or TT002, or their pharmaceutically acceptable salts, diastereomers, enantiomers, isotopes, prodrugs or metabolites, or mixtures thereof, for use. In one aspect, the animal is a horse. In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In another embodiment, the animal is a cat or a dog. In one aspect, the compound is TT001, or its hydrochloride or sulfate salt. Because the compounds act on the central nervous system, they can be used to treat and/or prevent pain and anxiety simultaneously. This is important before and during veterinary treatment of animals such as injections or surgery.

The invention relates to the treatment, prevention or risk reduction of pain such as chronic and/or peripheral pain and/or pain associated with arthritis such as osteoarthritis, or a) in combination with b) GERD or c) anxiety. TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, or protein thereof, to a dog, cat, or horse in need thereof. including administering a drug or metabolite, or a mixture thereof. In one aspect, the compound is TT001, or its hydrochloride or sulfate salt.

The present invention further provides compounds TT00, TT001 and/or TT002, or pharmaceutically acceptable salts, diastereomers, enantiomers, isotopes, prodrugs or metabolites thereof, or mixtures thereof. and a pharmaceutical composition containing the compound in combination with an adjuvant, diluent or carrier. In one aspect, the compound is TT001, or its hydrochloride or sulfate salt.

The present invention also provides compounds TT00, TT001 and/or TT002, or their pharmaceutically acceptable salts, diastereomers, enantiomers, isotopes, prodrugs or metabolites, or mixtures thereof. A method for preparing a pharmaceutical composition as defined above, comprising mixing with an adjuvant, diluent or carrier. In one aspect, the compound is TT001, or its hydrochloride or sulfate salt.

One aspect is a pharmaceutically acceptable drug for use in the prevention and/or treatment of pain, such as chronic and/or peripheral pain, and/or pain associated with arthritis, such as osteoarthritis, in dogs, cats, or horses. Compounds TT00, TT001 and/or TT002, or their pharmaceutically acceptable salts, diastereomers, enantiomers, isotopes, prodrugs or metabolites, or mixtures thereof, in combination with an adjuvant, diluent or carrier that A pharmaceutical composition comprising: In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In one aspect, the compound is TT001, or its hydrochloride or sulfate salt. In one embodiment, the animal is a dog. In another embodiment, the animal is a cat or a horse.

One aspect provides for the treatment of both a) pain, such as chronic and/or peripheral pain, and/or pain associated with arthritis, such as osteoarthritis, and b) gastroesophageal reflux disease (GERD) in dogs, cats, or horses. Compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, thereof, in combination with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in prophylaxis and/or therapy. It relates to pharmaceutical compositions containing enantiomers, isotopes, prodrugs or metabolites, or mixtures thereof. In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In one aspect, the compound is TT001, or its hydrochloride or sulfate salt. In one embodiment, the animal is a dog. In another embodiment, the animal is a cat or a horse. In another aspect, the pain is chronic and peripheral pain associated with osteoarthritis.

One aspect is for use in the prevention and/or treatment of both a) pain, such as chronic and/or peripheral pain, and/or pain associated with arthritis, such as osteoarthritis, and c) anxiety in dogs, cats, or horses. Compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug thereof, in combination with a pharmaceutically acceptable adjuvant, diluent or carrier for or a metabolite, or a pharmaceutical composition containing the mixture. In one aspect, the compound is TT001, or its hydrochloride or sulfate salt. In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In one embodiment, the animal is a dog. In another embodiment, the animal is a cat or a horse. In another aspect, the pain is chronic and peripheral pain associated with osteoarthritis.

The present invention also relates to the treatment of pain, such as chronic and/or peripheral pain, and/or pain associated with arthritis, such as osteoarthritis, in dogs, cats or horses, or a) in combination with b) GERD or c) anxiety. Use of the compounds TT00, TT001 and/or TT002, or their pharmaceutically acceptable salts, diastereomers, enantiomers, isotopes, prodrugs or metabolites, or mixtures thereof, in the manufacture of a medicament for pain. Regarding. In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In one aspect, the compound is TT001, or its hydrochloride or sulfate salt. In one embodiment, the animal is a dog. In another embodiment, the animal is a cat or a horse.

Compounds TT00, TT001 and/or TT002 may be administered at a dose of 0.1-5.0 mg/kg, or 0.1-2.0 mg/kg, or 0.1-1.0 mg/kg per day. can. One embodiment relates to a dosing regimen in which compounds TT00, TT001 and/or TT002 are administered to animals once or twice a day at a dose of 0.1 to 5.0 mg/kg. In one aspect, the compound is TT001, or its hydrochloride or sulfate salt. In one aspect, the dose is for prophylaxis and/or treatment in dogs.

In one aspect, the dosing regimen is administration of compounds TT00, TT001 and/or TT002 at a dose of 0.1-1.0 mg/kg once daily. In one aspect, the dosing regimen is administration of compounds TT00, TT001 and/or TT002 at a dose of 0.1-0.5 mg/kg twice daily. In one aspect, the compound is TT001, or its hydrochloride or sulfate salt.

As mentioned above, there is no disclosure of pain treatment in dogs, cats and horses using mGluR5 antagonists. Even in the TLESR studies, there is no mention of the effects of the compounds on pain relief. Clinical studies in humans have been discontinued.

The prevention and/or treatment of pain-related pathologies as defined herein may be applied as sole prevention and/or treatment or in addition to TT00, TT001 and/or TT002 as mentioned herein. can include co-treatment with conventional treatments useful for preventing and/or treating one or more disease conditions. Such conventional treatments may include one or more of the following categories of drugs: NSAIDs, anesthetics, and opiates. It is believed that TT00, TT001 and/or TT002 in combination with other analgesics may have synergistic effects on pain relief in animals, as well as additive effects due to dual treatment of different disease states.

In one aspect, the NSAID is selected from the group comprising or consisting of the class of pyrazolidines, which is 1,2-diphenylpyrazolidine-3,5-dione with a butyl group in the 4-position. It has a role as a non-narcotic analgesic, non-steroidal anti-inflammatory drug, anti-rheumatic drug, peripheral nervous system drug, metabolite and EC1.1.1.184 [carbonyl reductase (NADPH)] inhibitor. In another aspect, the NSAID is selected from the group comprising or consisting of butylpyrazolidine, oxicams, propionic acid derivatives, fenamic acids, coxibs and other non-steroidal anti-inflammatory and anti-rheumatic agents. In a further aspect, the NSAID is selected from the group comprising or consisting of oxicams, propionic acid derivatives and coxibs.

The opiate can be selected from the group comprising or consisting of tramadol or tapentadol.

Such joint treatment can be achieved by simultaneous, sequential or separate administration of the individual components of the treatment. Such combination products include compound TT00 for use in the prevention and/or treatment of pain, including chronic and/or peripheral pain, and/or pain associated with arthritis, such as osteoarthritis, in dogs, cats, or horses. , TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof, or a mixture thereof.

In one aspect, the present invention provides ( i) Compounds TT00, TT001 and/or TT002, or pharmaceutically acceptable salts, diastereomers, enantiomers, isotopes, prodrugs or metabolites thereof, or mixtures thereof; (ii) additional therapeutic agents; or A pharmaceutical composition comprising a pharmaceutically acceptable salt thereof, and (iii) a pharmaceutically acceptable excipient, carrier or diluent. In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In another aspect, the pain is chronic and peripheral pain associated with osteoarthritis. In one aspect, the compound is TT001, or its hydrochloride or sulfate salt. In one embodiment, the animal is a dog. In another embodiment, the animal is a cat or a horse.

In one aspect, the invention provides (i) compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof, or a mixture thereof; (ii) an additional therapeutic agent, or a pharmaceutically acceptable salt thereof; and (iii) ) A pharmaceutical composition comprising a pharmaceutically acceptable excipient, carrier or diluent. In one aspect, the pain is chronic pain associated with arthritis, such as osteoarthritis. In one aspect, the invention provides treatment for a) pain, such as chronic and/or peripheral pain, and/or pain associated with arthritis, such as osteoarthritis, and b) gastroesophageal reflux disease (GERD) in dogs, cats, or horses. (i) Compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof, for use in the prevention and/or treatment of both or mixtures thereof, (ii) an additional therapeutic agent, or a pharmaceutically acceptable salt thereof, and (iii) a pharmaceutically acceptable excipient, carrier or diluent. In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In another aspect, the pain is chronic and peripheral pain associated with osteoarthritis. In one aspect, the compound is TT001, or its hydrochloride or sulfate salt. In one embodiment, the animal is a dog. In another embodiment, the animal is a cat or a horse.

Anesthetics such as acepromazine have muscle-relaxing properties that affect the lower esophageal sphincter (LES), causing more reflux episodes during anesthesia. Simultaneous treatment of TT00, TT001 and/or TT002 with an anesthetic can improve the condition of an animal, at least in connection with veterinary treatment such as surgery.

In one aspect, the invention provides for the prevention and/or prevention of both a) pain, such as chronic and/or peripheral pain, and/or pain associated with arthritis, such as osteoarthritis, and c) anxiety in dogs, cats, or horses. or a compound TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof, or a mixture thereof, for use in therapy; (ii) a further therapeutic agent, or a pharmaceutically acceptable salt thereof; and (iii) a pharmaceutically acceptable excipient, carrier or diluent for use in the prophylaxis and/or treatment of both. PHARMACEUTICAL COMPOSITIONS. In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In another aspect, the pain is chronic and peripheral pain associated with osteoarthritis. In one aspect, the compound is TT001, or its hydrochloride or sulfate salt. In one aspect, the animal is a dog. In another embodiment, the animal is a cat or a horse. Although TT00, TT001 and/or TT002 are believed to treat both pain and anxiety, it may be advantageous to combine TT00, TT001 and/or TT002 with additional drugs to improve the condition of the animal. be. Also, as mentioned above, in combination with an anesthetic, TT00, TT001 and/or TT002 can improve the condition of an animal before, during and after veterinary treatment such as surgery. Compounds TT00, TT001 and/or TT002 are believed to have a positive effect on GERD. It may even be possible to use compounds TT00, TT001 and/or TT002 in combination treatment with NSAIDs, as they have been shown to affect GERD, which can be a serious side effect of NSAIDs. Since TT00, TT001 and/or TT002 act from the central nervous system and NSAIDs act from the peripheral nervous system, a combination of these two may have a synergistic effect on pain relief in animals, especially dogs. In one aspect, the compound is TT001, or its hydrochloride or sulfate salt.

In one aspect, the additional therapeutic agent is an NSAID, such as butylpyrazolidine, oxicam, propionic acid derivative, fenamic acid or coxib. In a further aspect, the NSAID is selected from the group comprising or consisting of oxicams, propionic acid derivatives and coxibs. In one aspect, the additional therapeutic agent is any other non-steroidal anti-inflammatory drug. In a further aspect, the NSAID is an anti-rheumatic drug. In one aspect, the additional therapeutic agent is an opiate, such as tramadol or tapentadol. In one aspect, the additional therapeutic agent is an anesthetic such as acepromazine, morphine or propofol.

In another embodiment, the invention relates to the prevention and/or treatment of pain, such as chronic and/or peripheral pain, and/or pain associated with arthritis, such as osteoarthritis, in dogs, cats, or horses; or b) GERD. or c) (i) the compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer thereof, for use in the prevention and/or treatment of both a) pain in combination with anxiety; , enantiomers, isotopes, prodrugs or metabolites, or mixtures thereof; (ii) at least one additional therapeutic agent selected from the group comprising or consisting of anesthetics, NSAIDs and opiates; and (iii) It relates to a pharmaceutical composition comprising a pharmaceutically acceptable excipient, carrier or diluent. In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In another aspect, the pain is chronic and peripheral pain associated with osteoarthritis. In one aspect, the compound is TT001, or its hydrochloride or sulfate salt. In one embodiment, the animal is a dog. In another embodiment, the animal is a cat or a horse.

In another embodiment, the invention relates to the prevention and/or treatment of pain, such as chronic and/or peripheral pain, and/or pain associated with arthritis, such as osteoarthritis, or in combination with b) GERD or c) anxiety. (i) Compounds TT00, TT001 and/or TT002, or pharmaceutically acceptable salts, diastereomers, enantiomers, isotopes thereof, for use in the prevention and/or treatment of a) said pain; a prodrug or metabolite, or a mixture thereof; (ii) at least one additional therapeutic agent that is an NSAID selected from the group comprising or consisting of oxicams, propionic acid derivatives, and coxibs; and (iii) a pharmaceutical The present invention relates to pharmaceutical compositions containing excipients, carriers or diluents that are acceptable to . In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In another aspect, the pain is chronic and peripheral pain associated with osteoarthritis. In one aspect, the compound is TT001, or its hydrochloride or sulfate salt. In one embodiment, the animal is a dog. In another embodiment, the animal is a cat or a horse.

In another embodiment, the invention relates to the prevention and/or treatment of pain, such as chronic and/or peripheral pain, and/or pain associated with arthritis, such as osteoarthritis, or in combination with b) GERD or c) anxiety. (i) Compounds TT00, TT001 and/or TT002, or pharmaceutically acceptable salts, diastereomers, enantiomers, isotopes thereof, for use in the prevention and/or treatment of a) said pain; a prodrug or metabolite, or a mixture thereof; (ii) at least one additional therapeutic agent that is another non-steroidal anti-inflammatory or anti-rheumatic agent; and (iii) a pharmaceutically acceptable excipient. It relates to a pharmaceutical composition comprising a carrier or diluent. In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In another aspect, the pain is chronic and peripheral pain associated with osteoarthritis. In one aspect, the compound is TT001, or its hydrochloride or sulfate salt. In one aspect, the animal is a dog. In another embodiment, the animal is a cat or a horse.

In another embodiment, the invention relates to the prevention and/or treatment of pain, such as chronic and/or peripheral pain, and/or pain associated with arthritis, such as osteoarthritis, or in combination with b) GERD or c) anxiety. (i) Compounds TT00, TT001 and/or TT002, or pharmaceutically acceptable salts, diastereomers, enantiomers, isotopes thereof, for use in the prevention and/or treatment of a) said pain; a prodrug or metabolite, or a mixture thereof; (ii) at least one additional therapeutic agent that is an opiate selected from the group comprising or consisting of tramadol and tapentadol; and (iii) a pharmaceutically acceptable It relates to pharmaceutical compositions containing excipients, carriers or diluents. In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In another aspect, the pain is chronic and peripheral pain associated with osteoarthritis. In one aspect, the compound is TT001, or its hydrochloride or sulfate salt. In one embodiment, the animal is a dog. In another embodiment, the animal is a cat or a horse.

In another embodiment, the invention relates to the prevention and/or treatment of pain, such as chronic and/or peripheral pain, and/or pain associated with arthritis, such as osteoarthritis, or in combination with b) GERD or c) anxiety. (i) Compounds TT00, TT001 and/or TT002, or pharmaceutically acceptable salts, diastereomers, enantiomers, isotopes thereof, for use in the prevention and/or treatment of a) said pain; a prodrug or metabolite, or a mixture thereof; (ii) at least one further therapeutic agent that is an anesthetic selected from the group comprising or consisting of acepromazine, morphine or propofol; and (iii) a pharmaceutical It relates to pharmaceutical compositions containing acceptable excipients, carriers or diluents. In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In another aspect, the pain is chronic and peripheral pain associated with osteoarthritis. In one aspect, the compound is TT001, or its hydrochloride or sulfate salt. In one aspect, the animal is a dog. In another embodiment, the animal is a cat or a horse.

Such combination products include compounds TT00, TT001 and/or TT002 within the dosage ranges described herein, and other additional therapeutic agents within the approved dosage ranges and/or reference publications thereof. Use the dosages listed in.

Pharmaceutical compositions comprising compounds TT00, TT001 and/or TT002, or their pharmaceutically acceptable salts, diastereomers, enantiomers, isotopes, prodrugs or metabolites, or mixtures thereof, optionally include the above. Can be administered topically or orally together with one or more additional therapeutic agents as defined. In one aspect, the pharmaceutical composition is administered topically. In another embodiment, the pharmaceutical composition is administered intramuscularly. In further embodiments, the pharmaceutical composition is administered intravenously.

The definitions provided in this application are intended to clarify terms used throughout this application. The term "this specification" refers to the entire application.

The expression "compounds TT00, TT001 and/or TT002" includes, unless otherwise specified, their pharmaceutically acceptable salts, diastereomers, enantiomers, isotopes, prodrugs or metabolites, etc., or mixtures thereof. I hope you understand that.

As used herein, "pharmaceutically acceptable salt" refers to a form of a disclosed compound in which the parent compound is modified by forming an acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali salts or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. Such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid. Examples of salts are hydrochlorides or sulfates, especially 4-[5-[(1R)-1-[5-(3-chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2, 4-triazol-3-yl]pyridine hydrochloride or 4-[5-[(1R)-1-[5-(3-chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2, 4-triazol-3-yl]pyridine sulfate.

As used herein, the phrase "or pharmaceutically acceptable salts" includes hydrates and solvates thereof.

Pharmaceutically acceptable salts of the invention can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or free base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or in a mixture of the two. Generally, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile are used.

Compounds TT00, TT001 and/or TT002, in particular TT001, can exist in certain geometric or stereoisomeric forms. The present invention covers all its tautomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof. Such compounds are considered to be included within the scope of this invention.

As used herein, "tautomer" refers to other structural isomers that exist in equilibrium resulting from migration of hydrogen atoms. For example, keto-enol tautomerism occurs when the resulting compound has the properties of both a ketone and an unsaturated alcohol.

The compounds TT00, TT001 and/or TT002, particularly TT001, and salts described herein may be isotopically labeled (or "radiolabeled"). In that case, one or more atoms are replaced by an atom having an atomic mass or mass number different from that normally found in nature (ie, naturally occurring). Examples of suitable isotopes that may be incorporated include ^2H (also written as "D" for deuterium), ^3H (also written as "T" for tritium), ^11C , ^13C , ¹⁴ C, ¹³ N, ¹⁵ N ^{, 15} O, ¹⁷ O, ¹⁸ O, ¹⁸ F, 35 S, ³⁶ Cl, ⁸² Br, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I and ¹³¹ I are Can be mentioned. The radionuclide used will depend on the particular application of the radiolabeled derivative. For example, compounds incorporating ³ H or ¹⁴ C are often useful for in vitro receptor labeling and competition assays. In radiographic imaging applications, ¹¹ C or ¹⁸ F are often useful. In some embodiments, the radionuclide is ^3H . In some embodiments, the radionuclide is ^14C . In some embodiments, the radionuclide is ^11C . In some embodiments, the radionuclide is ^18F . The present invention includes any isotope of TT00, TT001 and/or TT002 for use in animal diagnostics such as dogs, cats or horses.

Compounds TT00, TT001 and/or TT002, particularly TT001, can be administered orally, parenterally, bucally, vaginally, rectally, inhaled, insufflated, sublingually, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrapleurally, intravenously. It can be administered by epidural, intrathecal, intraventricular, and intraarticular injection. The compounds can be administered topically.

The optimal dosage and frequency of administration will depend on the particular condition being treated and its severity, the species, the age, sex, size and weight of the particular animal, its diet, and the general physical condition the animal is taking. It will depend on the possible other drugs, the route of administration, the formulation, and various other factors known to physicians and others skilled in the art.

Dosages can be readily ascertained by those skilled in the art from this disclosure and the knowledge of those skilled in the art. Accordingly, those skilled in the art can readily determine the amounts of compound and any additives, vehicles and/or carriers in the compositions to be administered in the methods of the invention.

The amount of compounds TT00, TT001 and/or TT002, particularly TT001, administered will vary for the dog, cat or horse being treated and will vary from about 0.01 ng/kg body weight to 10 mg/kg body weight per day. Compounds TT00, TT001 and/or TT002 may be administered at a dose of 0.1-5.0 mg/kg, or 0.1-2.0 mg/kg, or 0.1-1.0 mg/kg per day. can. One embodiment relates to a dosing regimen in which compounds TT00, TT001 and/or TT002 are administered to dogs, cats or horses at doses of 0.1 to 5.0 mg/kg once or twice a day. In one aspect, the compound is TT001, or its hydrochloride or sulfate salt.

In one aspect, the dosing regimen comprises administering the compound to a dog, cat or horse at a dose of 0.1-1.0 mg/kg once daily or 0.1-0.5 mg/kg twice daily. Administration of TT00, TT001 and/or TT002.

For preparing pharmaceutical compositions from compounds TT00, TT001 and/or TT002, particularly TT001, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form compositions include powders, tablets, dispersible granules, capsules, cachets, and suppositories. The solid carrier can be one or more substances that can also act as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, or tablet disintegrant, and can act as a encapsulating agent. It may be a material.

Liquid compositions include ointments, creams, gels, and aqueous liquids that can be formulated within transdermal patches.

The capsule preparation method includes the following steps:
a) mixing the compound TT00, TT001 or TT002, in particular TT001, with additives such as calcium hydride, phosphate and hydroxypropylcellulose and stirring for a certain period of time;
b) adding further additives such as mannitol and croscarmellose sodium;
c) adding water and granulating the mixture;
d) drying the obtained granules;
e) grinding the dry granules;
f) adding further additives such as sodium stearyl fumarate;
g) mixing the resulting mixture; and h) filling the mixture into capsules or pressing the mixture into tablets.

The pharmaceutical compositions can be used for the prevention and/or treatment of any disease state or combination of conditions mentioned herein.

Combination Therapy The prevention and/or treatment of pain-related pathologies as defined herein may be combined with conventional treatments of value in preventing and/or treating one or more disease conditions referred to herein. Can be applied. Such conventional treatments may include one or more of the following categories of additional therapeutic agents: NSAIDs, anesthetics, and opiates.

An example of an NSAID may be an NSAID selected from the group comprising or consisting of the class of pyrazolidines, which is 1,2-diphenylpyrazolidine-3,5-dione with a butyl group in the 4-position. It has a role as a non-narcotic analgesic, non-steroidal anti-inflammatory drug, anti-rheumatic drug, peripheral nervous system drug, metabolite and EC1.1.1.184 [carbonyl reductase (NADPH)] inhibitor. In a further aspect, the NSAID is selected from the group comprising or consisting of butylpyrazolidine, oxicams, propionic acid derivatives, fenamic acid and coxibs. The NSAID may be selected from the group comprising or consisting of oxicams, propionic acid derivatives and coxibs.

NSAIDs may include butylpyrazolidine, oxicams, propionic acid derivatives or coxibs. The additional therapeutic agent may be any other non-steroidal anti-inflammatory or anti-rheumatic agent.

Examples of opiates include tramadol and tapentadol.

Such co-therapy may include individual treatments for use in the prevention and/or treatment of pain, including chronic and/or peripheral pain, and/or pain associated with arthritis, such as osteoarthritis, in dogs, cats, or horses. This can be achieved by simultaneous, sequential or separate administration of the components.

The combination includes (i) compounds TT00, TT001 and/or TT002, or pharmaceutically acceptable salts, diastereomers, enantiomers, isotopes, prodrugs or metabolites thereof, or mixtures thereof; (ii) further It may comprise or consist of a pharmaceutical composition comprising a therapeutic agent, or a pharmaceutically acceptable salt thereof, and (iii) a pharmaceutically acceptable excipient, carrier or diluent.

The combination may also include (i) the compound TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof, or a mixture thereof; (ii) an anesthetic. a pharmaceutical composition comprising or consisting of at least one additional therapeutic agent selected from the group consisting of drugs, NSAIDs and opiates, and (iii) a pharmaceutically acceptable excipient, carrier or diluent. It's okay.

This definition of combination includes (i) compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof, or a mixture thereof; a pharmaceutically acceptable excipient, carrier or diluent, and (ii) at least one additional therapeutic agent selected from the group consisting of anesthetics, NSAIDs and opiates, and a pharmaceutically acceptable excipient. , a carrier or a diluent.

The combination may be (i) TT001, or its hydrochloride or sulfate, and (ii) acepromazine.

The combination may be (i) TT001, or its hydrochloride or sulfate, and (ii) oxicam. The combination may be (i) TT001, or its hydrochloride or sulfate, and (ii) a propionic acid derivative. The combination may be (i) TT001, or its hydrochloride or sulfate salt, and (ii) coxibs.

Additional therapeutic agents may be opiates such as tramadol and tapentadol.

The combination may be (i) TT001, or its hydrochloride or sulfate salt, and (ii) tramadol. The combination may be (i) TT001, or its hydrochloride or sulfate, and (ii) tapentadol.

The further therapeutic agent may be an anesthetic selected from the group comprising or consisting of acepromazine, morphine or propofol.

The combination may be (i) TT001, or its hydrochloride or sulfate, and (ii) acepromazine. The combination may be (i) TT001, or its hydrochloride or sulfate salt, and (ii) morphine. The combination may be (i) TT001, or its hydrochloride or sulfate salt, and (ii) propofol.

The combination is for the prevention and/or treatment of pain such as chronic and/or peripheral pain and/or pain associated with arthritis such as osteoarthritis, or both of a) such pain in combination with b) GERD or c) anxiety. It may be used for the prevention and/or treatment of.

Pharmaceutical composition Ointment Active substance corresponding to the weight of TT001: 0.1-50 mg
Weight of propylene carbonate: 50mg
Weight of solid paraffin: 30mg
Weight of white beeswax: 35mg
Weight of liquid paraffin: 110mg
Weight of white soft paraffin: 774.7mg

Cream TT001 weight: 0.1-100mg
Weight of propylene glycol: 100mg
Weight of isopropyl myristate: 50mg
Weight of cetostearyl alcohol: 52.5mg
Weight of citric acid monohydrate (e330): 0.5mg
Weight of anhydrous disodium phosphate: 0.6 mg
Weight of water: Add enough to achieve target weight of 30 or 100g Weight of liquid paraffin: 400mg
Weight of macrogol cetostearyl ether: 7.5mg
Weight of disodium phosphate dodecahydrate (e339): 1.5 mg
Weight of imidourea: 2mg

capsules

Preparation of Compounds Compounds TT00, TT001 and/or TT002 can be prepared by preparing the free base or its It can be prepared as a pharmaceutically acceptable salt.

Pharmaceutical Composition Method of Formulation for the Preparation of TT001 for Intravenous Administration at 0.1-10 mg/ml The method of formulation is from 0.1 mg/mL corresponding to 0.262 μmol/mL to 26.2 μmol/mL. Applicable at a concentration in the formulation of 10 mg/mL.
TT001's M. W. :381.8g/mol
Dissolution of TT001 is moderate and complete dissolution takes several hours.
Vehicle Preparation of a 40% w/v HPβCD solution in water for injection Excipients Hydroxypropyl-β-cyclodextrin, kleptose, Roquette (HPβCD) 400 mg (40% w/v)
1 ml (1.13 g) of water for injection
Appearance Transparent Density 1.13 g/cm3

Formulation Preparation of 0.1-10 mg/ml TT001 intravenous formulation TT001 parent form 0.1-10 mg
Vehicle (40% w/v HPβCD solution in water for injection) up to 1 ml (1.13 g) Appearance Clear Density 1.13 g/cm ³

Comments The dissolution of TT001 is moderate and complete dissolution takes several hours.

Active substance corresponding to the weight of ointment TT001: 0.1-50 mg
Weight of propylene carbonate: 50mg
Weight of solid paraffin: 30mg
Weight of white beeswax: 35mg
Weight of liquid paraffin: 110mg
Weight of white soft paraffin: 774.7mg

Cream TT001 weight: 0.1-100mg
Weight of propylene glycol: 100mg
Weight of isopropyl myristate: 50mg
Weight of cetostearyl alcohol: 52.5mg
Weight of citric acid monohydrate (e330): 0.5mg
Weight of anhydrous disodium phosphate: 0.6 mg
Weight of water: Add enough to achieve target weight of 30 or 100g Weight of liquid paraffin: 400mg
Weight of macrogol cetostearyl ether: 7.5mg
Weight of disodium phosphate dodecahydrate (e339): 1.5 mg
Weight of imidourea: 2mg

capsules

Example Pharmaceutical composition Ointment Weight of TT001: 0.1 to 100 mg
Weight of propylene carbonate: 50mg
Weight of solid paraffin: 30mg
Weight of white beeswax: 35mg
Weight of liquid paraffin: 110mg
Weight of white soft paraffin: 774.7mg

Cream TT001 weight: 0.1-100mg
Weight of propylene glycol: 100mg
Weight of isopropyl myristate: 50mg
Weight of cetostearyl alcohol: 52.5mg
Weight of citric acid monohydrate (e330): 0.5mg
Weight of anhydrous disodium phosphate: 0.6 mg
Weight of water: Add enough to achieve target weight of 30 or 100g Weight of liquid paraffin: 400mg
Weight of macrogol cetostearyl ether: 7.5mg
Weight of disodium phosphate dodecahydrate (e339): 1.5 mg
Weight of imidourea: 2mg

Pain Relief Experiments The following protocols can be used to assess pain relief in dogs: - Kinetic data using force plates and pressure walkways - Helsinki Chronic Pain Index (HCPI)
-Canine Simple Pain Inventory (CBPI)
-Cincinnati Orthopedic Disease Index (CODI)
- As per Liverpool Osteoarthritis of Dogs (LOAD).

Chronic pain is also assessed by the owner, so so-called "owner questionnaires" are very often used for evaluating the effectiveness of pain products.

Canine gait analysis is an important tool for objectively assessing normal and abnormal gait. Although there are many methods for collecting temporal and spatial parameters for gait analysis, currently force plates (FPs) are used to measure ground reaction forces (GRFs) and related metrics generated from those forces. considered the gold standard. Data collected from FP has proven to be an effective method for assessing lameness and the success or combination of medical or surgical interventions in dogs with musculoskeletal pathologies.

Example 1
To be able to assess pain, valid pain models can be used, such as kinetic data using force plates and/or pressure walkways. This should be combined with a valid pain protocol such as the Helsinki Chronic Pain Index (HCPI), the Canine Brief Pain Assessment (CBPI) or the Liverpool Osteoarthritis in Dogs (LOAD).

Study To be included in the study, the dog must have OA and the veterinarian will decide whether the dog should be included in the study.

Owners will answer questions according to protocol at the first meeting.

The owner's dog with OA is then led to a pressure walkway with gyros attached to its legs and head. The pressure on the pavement as well as data from the gyro are recorded. Walking will also be videotaped.

Dogs with OA will put more weight on the unaffected limb as they walk, and this is recorded by both the pressure walk and the gyro.

After the first walk, dogs are dosed with TT001, prepared as an oral or topical transdermal formulation, and then sent home. A week later, the owner returns the dog. During the week the dog is being medicated with TT001 by the owner.

At the second meeting, a week later, the dogs walk the sidewalk again. The owner will answer the questions according to the protocol.

The third and final meeting will be a week later and the procedure will be the same as the previous week.

Data from the sidewalk, gyro, and video are processed. The algorithm compares different datasets and presents any differences in dog gait. This then forms the basis for the evaluation of the effect of TT001 on pain.

This example is expected to show that TT001 indeed has an effect on pain in dogs with OA and does not have the toxic effects known from NSAIDs.

Example 2
The toxic effects of NSAIDs are caused in part by inhibition of prostaglandin production, which protects renal and gastrointestinal homeostasis. Cats are particularly susceptible to the toxic effects of some NSAIDs because they lack the hepatic glutathione-dependent enzyme system involved in the metabolism of many NSAIDs. Toxic side effects include vomiting, gastric irritation progressing to ulceration and bleeding, enteritis leading to diarrhea, blood disorders, and sometimes hepatotoxicity and/or nephrotoxicity. Nephrotoxicity is more likely to occur in dehydrated, hypovolemic or hypotensive animals, animals undergoing anesthesia, or animals treated with other potentially nephrotoxic drugs.

It should be understood that older cats suffer from osteoarthritis (OA) more often than younger cats, and these older cats have a much higher incidence of kidney problems. Because treatment for OA is lifelong, it is important that medications do not adversely affect the cat's kidneys. TT001 showed no adverse effects on the kidneys.

The inventors intend to demonstrate in a clinical trial that cats with OA receive pain relief after being dosed with TT001.

To be able to assess pain, valid pain models can be used, such as kinetic data using force plates and/or pressure walkways. This should be combined with a valid pain protocol such as the Helsinki Chronic Pain Index (HCPI), the Canine Brief Pain Assessment (CBPI) or the Liverpool Osteoarthritis in Dogs (LOAD).

Study To be included in the study, the cat must have OA and the veterinarian will decide whether the cat should be included in the study.

Owners will answer questions according to protocol at the first meeting.

The owner's cat with OA is then led to a pressure walkway with gyros attached to its legs and head. The pressure on the pavement as well as data from the gyro are recorded. Walking will also be videotaped.

Cats with OA will put more weight on the unaffected limb as they walk, and this is recorded by both the pressure walk and the gyro.

After the first walk, cats are dosed with TT001, prepared as an oral or topical transdermal formulation, and then sent home. A week later, the owner returns the cat. During the week, the cat has been medicated with TT001 by the owner.

At the second meeting, a week later, the cat walks the sidewalk again. The owner will answer the questions according to the protocol.

The third and final meeting will be a week later and the procedure will be the same as the previous week.

Data from the sidewalk, gyro, and video are processed. The algorithm compares different datasets and presents any differences in cat gait. This then forms the basis for the evaluation of the effect of TT001 on pain.

This example is expected to show that TT001 indeed has an effect on pain in cats with OA and does not have the toxic effects known from NSAIDs.

Claims (16)

Compound 4-[5- [(rac)-1-[5-(3-chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine (TT00), 4-[5 -[(1R)-1-[5-(3-chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine, (TT001) and/or 4-[5-[(1S)-1-[5-(3-chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine (TT002) or a pharmaceutically acceptable salt, enantiomer, isotope, or mixture thereof. A pharmaceutically acceptable adjuvant for use in the prevention and/or treatment of both a) chronic and distal pain associated with peripheral pain or osteoarthritis and b) gastroesophageal reflux disease (GERD) in dogs; A pharmaceutical composition comprising a compound TT00, TT001 and/or TT002 according to claim 1 in combination with a diluent or carrier. In combination with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the prevention and/or treatment of both a) chronic and peripheral pain associated with peripheral pain or osteoarthritis and c) anxiety in dogs. and a pharmaceutical composition comprising the compound TT00, TT001 and/or TT002 according to claim 1 . (i) Compound 4-[5-[(rac)-1-[5-(3- Chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine (TT00), 4-[5-[(1R)-1-[5-(3 -chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine, CAS number 934282-55-0 (TT001) and/or 4-[5-[ (1S)-1-[5-(3-chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine (TT002), or its pharmaceutical an acceptable salt, enantiomer, isotope or mixture thereof, and a pharmaceutically acceptable excipient, carrier or diluent; and (ii) at least one selected from the group consisting of anesthetics, NSAIDs and opiates. A pharmaceutical composition comprising an additional therapeutic agent and a pharmaceutically acceptable excipient, carrier or diluent. (i) Compound 4-[5-[(rac)-1-[5-(3- Chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine (TT00), 4-[5-[(1R)-1-[5-(3 -chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine, (TT001) and/or 4-[5-[(1S)-1-[ 5-(3-chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine (TT002), or its pharmaceutically acceptable salt, enantiomer, A pharmaceutical composition comprising an isotope, or a mixture thereof, (ii) an additional therapeutic agent, or a pharmaceutically acceptable salt thereof, and (iii) a pharmaceutically acceptable excipient, carrier or diluent. ( i ) for use in the prevention and/or treatment of both a) chronic and peripheral pain associated with peripheral pain or osteoarthritis and b) gastroesophageal reflux disease (GERD) in dogs . A pharmaceutical composition comprising compounds TT00, TT001 and/or TT002 as described in . (i) a compound TT00 according to claim 4 or 5 for use in the prevention and/or treatment of both a) chronic and peripheral pain associated with peripheral pain or osteoarthritis and c) anxiety in dogs; A pharmaceutical composition comprising TT001 and/or TT002. 8. A pharmaceutical composition according to any one of claims 5 to 7, wherein the further therapeutic agent is an anesthetic, an NSAID or an opiate. 8. A pharmaceutical composition according to any one of claims 5 to 7, wherein the further therapeutic agent is an NSAID selected from the group comprising butylpyrazolidine, oxicams, propionic acid derivatives, fenamic acids and coxibs. 8. A pharmaceutical composition according to any one of claims 5 to 7, wherein the further therapeutic agent is an anesthetic selected from the group comprising acepromazine, morphine and propofol. 8. A pharmaceutical composition according to any one of claims 5 to 7, wherein the further therapeutic agent is an opiate selected from the group comprising tramadol and tapentadol. 12. The pharmaceutical composition according to any one of claims 1 to 11 , wherein the compound is TT001, or a hydrochloride or sulfate thereof. Pharmaceutical composition according to any one of claims 1 to 11 , wherein the compounds TT00, TT001 and/or TT002 are administered to dogs at a dose of 0.1 to 5.0 mg/kg. Pharmaceutical composition according to any one of claims 1 to 11 , wherein the compounds TT00, TT001 and/or TT002 are administered to dogs at a dose of 0.1 to 1.0 mg/kg once a day. . Pharmaceutical composition according to any one of claims 1 to 11 , wherein the compounds TT00, TT001 and/or TT002 are administered to dogs at a dose of 0.1 to 0.5 mg/kg twice a day. . A pharmaceutical composition according to any one of claims 1 to 11 , wherein compound TT001 is administered to dogs at a dose of 0.1 to 1.0 mg/kg once a day.